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Pegylated interferon alfa-2b provides minimal benefit as maintenance therapy for osteosarcoma
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The addition of pegylated interferon alfa-2b maintenance therapy to chemotherapy with methotrexate, doxorubicin and cisplatin did not statistically improves EFS in patients with osteosarcoma, according to the results of a phase 3 study.
Further, a large number of patients reported never starting or prematurely ceasing treatment with pegylated interferon alfa-2b, the researchers also reported.
Matthew R. Sydes, MSc, senior scientist and senior medical statistician in the Medical Research Council clinical trials unit at University College London, and colleagues conducted the randomized, controlled EURAMOS-1 trial to assess the benefit of pegylated interferon alfa-2b (IFN-α-2b) maintenance therapy for patients with resectable high-grade osteosarcoma who achieved a good histologic response to induction chemotherapy.
The initial analysis included 2,260 international patients aged 40 years or younger diagnosed with resectable high-grade osteosarcoma between 2005 and 2011. Patients eligible for good response random assignment had two or more preoperative cycles of methotrexate, doxorubicin and cisplatin (MAP) chemotherapy; macroscopically complete primary tumor surgery; less than 10% viable tumor remaining after surgery and no disease progression.
Of 1,041 confirmed good responders, 716 patients (median age, 14 years; 59% men) agreed to random assignment. Eighty-eight percent (n = 630) of patients had localized disease and 12% (n = 86) had primary metastases.
The researchers randomly assigned patients to receive four additional cycles of MAP with (n = 359) or without (n = 357) subcutaneous IFN-α-2b (0.5-1 µg/kg weekly after chemotherapy for up to 2 years post-registration).
Median follow-up for both treatment arms was 44 months.
EFS served as the primary endpoint. OS and toxicity served as secondary endpoints.
Twenty-three percent of patients assigned IFN-α-2b (n = 82) reported never starting treatment, the majority of whom did not start treatment due to treatment refusal (78%).
Further, of the 271 patients who initiated treatment with IFN-α-2b, 39% (n = 105) prematurely ceased treatment. The most common reasons for treatment cessation included toxicity (n = 47; 45%), disease progression (n = 25; 24%), patient choice (n = 18; 17%) and clinician choice (n = 7; 7%).
Nearly half of patients (n = 132; 49%) who received treatment with IFN-α-2b required dose reductions or delays. The median duration of therapy was 67 weeks (interquartile range [IQR], 25-75).
The researchers observed a 3-year EFS rate of 76% (95% CI, 72-79) among all patients and estimated an HR for IFN-α-2b treatment effect of 0.83 (95% CI, 0.61-1.12).
EFS rates at 3 years did not statistically differ between patients who received MAP plus IFN-α-2b vs. MAP monotherapy (77% vs. 74%).
Of the 176 events reported, the most common first events included metastases (MAP, n = 79; MAP plus IFN-α-2b, n = 70) and local recurrence (n = 11 for both arms). One patients on the MAP monotherapy arm had a secondary malignancy (acute myeloid leukemia) as a first event.
Eighty-four deaths occurred (MAP, n = 46; IFN-α-2b, n = 38; early estimated HR = 0.77; 95% CI, 0.5-1.19).
Patients in both treatment arms achieved similar 5-year OS rates (81% vs. 84%) and researchers continue to monitor survival data for follow-up.
One patient in the MAP monotherapy arm died from toxicity (cardiomyopathy), whereas no patients in the IFN-α-2b arm experienced fatal toxicities. Thirty-eight percent (n = 101) of patients in the IFN-α-2b arm experienced grade 3 toxicity as their worst toxicity and 12% (n = 38) experienced grade 4 toxicity as their worst toxicity.
Further, three serious adverse events related to IFN-α-2b occurred: two cases of left ventricular systolic dysfunction and one knee joint effusion.
“Although we have reached the target number of EFS events, ongoing follow-up of patients is crucial and will permit the planned analysis of OS,” Sydes and colleagues concluded. “The current EFS results, reported at the protocol-defined analytic endpoint, do not support the routine use of IFN-α-2b maintenance after standard chemotherapy for osteosarcoma." – by Cameron Kelsall
Disclosure: Sydes reports honoraria and travel expenses from Eli Lilly and research funding from Astellas, Janssen-Cilag, Pfizer, Novartis and Sanofi-Aventis. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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